Trypanosoma cruzi: susceptibility to chemotherapy with benznidazole of clones isolated from the highly resistant Colombian strain

Abstract

The present investigation was performed to evaluate the susceptibility of seven clones isolated from the highly resistant Colombian strains, prototype of Biodeme Type III. Seven clones previously obtained, showed a phenotypic homogeneity and high similarity with the parental strain. Eight groups of 30 mice were inoculated with one of seven clones or the parental strain; 20 were treated with benznidazole (100mg/kg/day) and 10 were untreated controls. Cure evaluations were done by parasitological and serological tests and PCR. Cure rates varied from 0% (null) to 16.7%. Correlation between positivity of parasitological and serological tests with positive PCR reached 37%. The results demonstrated the high resistance of the clones, suggesting the predominance of a highly resistant principal clone in this strain. The findings apparently indicate that the possibility of cure is minimal for patients infected with this biodeme; a fact that could affect the control of Chagas' disease through treatment of chronically infected people.

In vitro and in vivo experimental models for drug screening and development for Chagas disease

“…Due to the broad spectrum of bioactivity of various drugs in different stocks of T. cruzi (Brener & Chiari 1967, Brener et al 1976, Andrade et al 1977, Filardi & Brener 1984, Camandaroba et al 2003, it is important to analyse the activity of new compounds against parasites of different lineages, including strains resistant to Bz and nifurtimox (Andrade et al 1985, Filardi & Brener 1987. However, one of the main limitations of such an analysis is the difficulty of using different subpopulations of T. cruzi, including the Y and Colombian strains transfected with β-galactosidase, other enzymes or green fluorescent protein.…”

“…If the performance of a given compound or extract is similar or better than that of Bz at 100 mg/kg/day following the same treatment protocol, it will advance to the next stage of the screening process. PCR was identified as one of the necessary criteria because it is more sensitive and time efficient than haemoculture (Camandaroba et al 2003, Caldas et al 2008a, Miyamoto et al 2008) and it reduces the technicians' levels of exposure to the parasite. The use of cyclophosphamide to enhance the sensitivity of the parasitological cure analysis was also discussed because immunosuppressed animals that experience therapeutic failure quickly recover their high levels of parasitaemia (Bustamante et al 2008, Santos et al 2008.…”

Response to chemotherapy with benznidazole of clones isolated from the 21SF strain of Trypanosoma cruzi (biodeme Type II, Trypanosoma cruzi II)

“…The challenge for the chemotherapy of Chagas' disease is to detect drugs that could eliminate the more resistant clones present in the strains with high or medium susceptibility, as represented by biodeme Type II (T. cruzi II) and for the overall resistant clones of the biodeme Type III (T. cruzi I) strains, as recently demonstrated by Camandaroba et al 6 .…”

Sensibilidad al benzonidazol de cepas de Trypanosoma cruzi sugiere la circulación de cepas naturalmente resistentes en Colombia

“…Si bien es cierto que se han producido algunos avances en este sentido (7,12,13,41,42), en la actualidad aún no se han podido esclarecer parámetros tales como cuáles son las concentraciones del medicamento para considerar las cepas como resistentes y cuál es la relación entre los mecanismos de resistencia natural y la inducida. Además, existen pocos reportes sobre la correlación de la sensibilidad al benzonidazol con parámetros biológicos y genéticos del parásito, como la diversidad filogenética y la sensibilidad natural e inducida, entre otros, y los resultados obtenidos de estos estudios son controversiales (22,(43)(44)(45)(46).…”

“…La enfermedad de Chagas, causada por el parásito Trypanosoma cruzi, afecta, al menos, 7'694.500 personas de diferentes regiones del continente americano, con, aproximadamente, 70 millones en riesgo de contraer la infección y causa cerca de 45.000 muertes anuales (1,2). En Colombia, se estima que cerca del 5 % de la población se encuentra infectada con el parásito y, aproximadamente, el 11 % está en riesgo de contraer la infección (3,4).…”